Download The Health Effect of Psychostimulants: A Literature Review

Pharmaceuticals 2010, 3, 2333-2361; doi:10.3390/ph3072333
OPEN ACCESS
pharmaceuticals
ISSN 1424-8247
www.mdpi.com/journal/pharmaceuticals
Review
The Health Effect of Psychostimulants: A Literature Review
Thierry Favrod-Coune * and Barbara Broers
Division of Primary Care Medicine, Geneva University Hospitals 4, Rue Gabrielle-Perret-Gentil,1211
Geneva 14, Switzerland; E-Mail: [email protected] (B.B.)
* Author to whom correspondence should be addressed; E-Mail: [email protected]
(T.F.C.); Tel.: +41-22-372-9537; Fax: +41-22-372-9512.
Received: 2 June 2010 / Accepted: 21 July 2010 / Published: 22 July 2010
Abstract: Prevalence of psychostimulant use is high, and raising in several countries.
Nicotine is the legal stimulant causing the most important public health impact. Cocaine
ranks among the most used illicit substances after cannabis. Stimulant medications are
frequently misused. Psychostimulants can lead to addiction, have physical, psychological
and social health consequences and can induce a great disease burden. The aim of the
present article is to provide a literature review on the health effects of stimulants as
potential drugs of abuse. It will cover essentially cocaine, amphetamines and its derivatives
(including methamphetamines and 3-4-methylenedioxymethamphetamine, ecstasy),
nicotine, caffeine and khat, and touch upon the issues of prescribed substances (antidepressants, weight control medications, attention-deficit hyperactivity disorder
medications, hypersomniac disorder). Their pharmacology, addictive potential, health
consequences and treatment will be discussed. We used Medline for the literature review
from 1990 to the date of this review, and mention the findings of human and animal studies
(the latter only if they are of clinical relevance).
Keywords: psychostimulants; cocaine; amphetamines; ecstasy (MDMA); nicotine;
caffeine; khat
1. Introduction
Psychostimulants are the most used psychotropic substances over the world. A “psychostimulant”
can be defined as a psychotropic substance with the capacity to stimulate the central nervous system. It
causes excitation and elevated mood, as well as increased alertness and arousal. Its global effect is to
Pharmaceuticals 2010, 3
2334
speed up signals into the brain. A psychostimulant can also be negatively defined as a substance other
than a depressant or a hallucinogenic substance.
Beyond the worldwide use of caffeine and nicotine, illicit psychostimulants are more used in
specific subgroups or cultures. Cocaine may be used in private parties as a mood and energy enhancer,
methamphetamines (speed, ice) in raves or techno culture for the same reasons, and 3-4-methylenedioxymethamphetamine (ecstasy), also known as the “love pill” in a wish to enter an empathic state.
Recently, in the context of an always more individual and competitive society, the use of cocaine or
methamphetamine in the professional context has been observed. A certain plant, khat, is used in
specific societies in east-Africa for its psychostimulant properties. Psychostimulants (e.g. sibutramine)
can be prescribed to lower appetite in obesity. This can be considered the pharmacologic part of the
treatment of a huge epidemic of obesity (BMI > 30) which increased from 23% of the population in the
period of 1988-1994 to 31% in the period 1999-2000 in the USA [1]. The other indication for
prescribed psychostimulants (e.g. methylphenidate) is attention-hyperactivity disorder in children (US
prevalence 8.3% in children aged 8-15 year old [2]) or adults (4.4% of adults aged 18-44 year old [3]).
The very rare disorder narcolepsy (25-50 per 100,000 persons [4]) can warrant psychostimulant
prescription (e.g. methylphenidate, modafinil or amphetamines) for the treatment of daytime
sleepiness. Finally, the group of selective serotonin reuptake inhibitors and other amine reuptake
inhibitors (noradrenalin) are widely used as anti-depressants but act more as correctors of an abnormal
slow function of the central nervous system activity as stimulants in a direct sense of the term [5].
Caffeine is the most consumed socially acceptable stimulant, with approximately 90% of the
population who consume it daily in the industrialized countries. Nicotine can be considered the most
used legal stimulant with 25% of the population who use it daily in Western Europe, and 17.5% in the
United States of Americas. For nicotine, the percentages are even higher in Eastern Europe and South
America, and with a clear male predominance [6]. When we consider the illicit substances, the
prevalence of consumption in the last year for the adult (15-64 year old) population is also quite
impressive: in Europe it is estimated to be 1.3% of adults for cocaine, 0.8% for ecstasy, and 0.6% for
amphetamines. The total prevalence for illicit psychostimulant use over the last 12 months will then be
about 2.7% of the population last year [7]. The situation in the United States of Americas shows that
cocaine (including crack) has been consumed in the last year by 7.5% of the young adults
(18-25 year old), 2.2% for the younger (12-17 year old) and 2.5% for the older (26 year old and older).
These percentages are respectively 3.7%, 1.3% and 0.3% for ecstasy, and 1.6%, 0.7% and 0.4% for
methamphetamines [8]. Comparing to Europe the amount of people consuming illicit psychostimulants
altogether in USA is more important, with about 4.5% of people using cocaine in the last year.
The WHO World Mental Health Survey Initiative followed over 85,000 people in 17 countries
around the world. They found that life-time prevalence of cocaine use varied between 0 and 16%, the
lowest being in China, Japan and Nigeria, and the highest being in the USA. Of interest is that the
distribution is not even and cannot simply be explained by drug control policies, since country with the
most severe illegal drug policies do not have lower levels of consumption than the ones with more
liberal ones [9].
In a report of the National Department of Health [3], the prescribed stimulants used in the United
States of Americas are found to be at the level of 3.5% of the young adults (18-25 year old), 2.3% for
the younger (12-17 year old) and 0.6% for the older (26 year old and older).
Pharmaceuticals 2010, 3
2335
The rationale for this review is to provide a comprehensive and synthetic review in English of all
psychostimulants in a clinical perspective. To our knowledge several reviews on separate substances
have been published, as well as a more global overview in French [10], but no global and recent
overview is available. We focused on the pharmacology of each product, its addictive potential, its
health consequences and the different treatment options usually admitted in case of problematic use.
We will present the different substances in order of decreasing prevalence of use in Western
countries, independently of their legal status. The last section concerns the special issue of prescribed
psychostimulants.
2. Experimental Section
2.1. Methods
We have used the Cochrane database and Medline for a selective literature review from 1990 to the
date of this review. If few articles were available we used earlier publications to complete. The terms
inserted include “psychostimulants”, “cocaine” and “crack cocaine”, “amphetamines”,
“methamphetamines”, “MDMA” and “ecstasy” (3-4-ethylenedioxymethamphetamine), “khat”,
“nicotine”, “caffeine”, “appetite suppressant” and “weight control medication”, “attention-deficit
hyperactivity disorder medication”, and finally “hypersomniac state medication”. We used the
findings of human and animals studies, but only if they are of clinical relevance.
3. Results and Discussion
3.1. Caffeine
Caffeine is a natural alkaloid found in plants, exactly 1,3,7-trimethylxanthine. Coffee and tea, the
most widely consumed psychostimulants in the world, contain several chemical components that can
be responsible for beneficial and adverse health effects, including caffeine and antioxidants (e.g.
polyphenols, catechins and flavonoids) and other unidentified substances that activate the sympathetic
system [11]. In Europe, the typical dose for a cup a coffee is 60-70 mg of caffeine, and about 35 mg
for a cup of tea, while a glass of coca cola contains about 46 mg and an energy drink about 80 mg [12].
In the United States, the average consumption of caffeine is 280 mg per day, which is the equivalent
of 2 cups per day. People taking four or more cups are considered as heavy coffee users. Coffee is
preferred to tea in most developed countries (except in England and Ireland) where 71.5% of the
worldwide coffee consumption [13] is used. Tea is preferred to coffee in the developing countries,
particularly in Argentina, Chile, Paraguay and Uruguay, and in Asia. These countries count for 76.6%
of the tea consumption in the world. The total quantity of tea consumed is much higher than coffee,
and tea is thus the second beverage consumed after water.
Caffeinated soft drinks are also emerging source of caffeine intake, especially for teenagers. The
caffeine content in these drinks can vary between 50 to 500 mg per can or bottle [14]. We will not
discuss here substances that can be added to caffeinated beverages and potentially change their health
properties, such as cream, milk or sugar.
Pharmaceuticals 2010, 3
2336
Caffeine is rapidly absorbed and undergoes demethylation in the liver via the enzyme cytochrome
P450 1A2. Defect of this enzyme is associated with prolonged caffeine half-life [15]. The genetic
polymorphism in this pathway may explain differences in outcomes of studies about caffeine and its
health consequences. Once in the blood, caffeine exerts its action as a potent antagonist of central and
peripheral nervous system adenosine receptors. As these act as inhibitory neurotransmitters, caffeine
stimulates excitatory neurotransmitters [16].
Several benefits can be attributed to caffeine-containing beverages. Neuro-psychological effects of
caffeine are increased alertness, energy and concentration, especially if consumers are tired or night
workers [17-18]. It has been suggested in a randomized study that caffeine also improves mood and
working memory [19], even if some authors have postulated that these effects would be attributable to
the reversal of effects due to caffeine withdrawal [20].
Somatic consequences of caffeine include a proven analgesic effect for tension or migraine
headache at a dose superior to 65 mg [21], even if caffeine is also a potential cause of chronic migraine
and rebound headache if chronically consumed [22]. A dose-effect relationship for the protection
towards Parkinson’s disease [23] has been suggested, as is an association with a reduction of risk for
Alzheimer’s disease [24] (relative risk of 0.7). There might also be also a protective effect of caffeine
for myocardial infarction, even if it can trigger arrhythmia [25] and coronary events [26] in very
susceptible individuals, probably depending on the personal caffeine metabolism (slow metabolisers
being at higher risk). Caffeine containing beverages can raise the blood pressure in non-tolerant
individuals, but has no long term effect on blood pressure in daily consumers [27]. Concerning the
glucose metabolism, several prospective long term studies have shown that consumption of coffee or
tea is associated with an improved insulin sensitivity, also in the diabetic patient [28-29], with a clear
preventive action against type 2 diabetes, in normal subjects or in those with impaired glucose
tolerance [30-31]. A strong inverse dose-dependent relationship between coffee drinking and alcoholic
cirrhosis has been shown in a large US cohort study (relative risk ranging from 0.6 95% CI 0.6-0.8 for
1-3 cups per day to 0.2, 0.1-0.4 for drinkers of more than 4 cups) [32]. Coffee consumption seems to
reduce the incidence of gout in a dose dependent manner [33]. Physical capacities are also ameliorated
by caffeine [34] with a maximal benefit at a dose of 2-3 mg/kg. High caffeine intake used to be
considered as doping, with a limitation of 2 to 3 cups of coffee per day (or equivalent), but this has
been abandoned (ref: www.wada-ama.org).
Considering all-cause mortality, it has been shown in large cohort studies [35] (more than
100,000 persons followed for 18 years at minimum) that all-cause mortality was reduced at a relative
risk of 0.8 for men (95% CI 0.62-1.04) and 0.83 for women (95% CI 0.73-0.95). The borderline
statistical insignificance for men warrants further study. Most of this mortality reduction was due to a
diminished cardiovascular mortality. There would be reasons to postulate that caffeine decreases risk
of cancer because of its antioxidant properties, but this never has been proven scientifically, and study
results are conflicting [36].
Negative consequences of caffeine include an increased risk for osteoporosis, and possibly for bone
fracture, in particular for women with low calcium intake and high caffeine intake [37-38]. A link with
increased risk of anxiety symptoms has been suggested, but evidence of causality is lacking.
Nevertheless, caffeine has been associated with anxiety, nervousness, irritability, insomnia and even
Pharmaceuticals 2010, 3
2337
panic attacks [39-40]. In people suffering from anxiety or stress disorders, caffeinated beverages
should be discussed, and discouraged if symptoms are found to be worsened by caffeine.
The abuse or dependence potential of caffeine has not been convincingly demonstrated [41], and
there is little evidence to say that tolerance develops [42]. For these reasons, no diagnosis of caffeine
dependence exists in the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) [43].
Still, it is clear that a caffeine withdrawal syndrome does exist. It is benign, with the principal
symptoms being headache, tiredness, decreased attentiveness and contentedness [44]. This happens to
50% of people who stop drinking coffee; the most frequent symptom is the headache. It may happen
from a dose as low as 100 mg/day and develop within 12 to 24 hours after the last dose. It lasts
normally 1 or 2 days, but may persist as long as 9 days. A progressive reduction of caffeine intake is
recommended if abstinence is planned, but no substitution is necessary if an unplanned abstinence
occurs.
Summing up: caffeine has probably more advantages than risks for health, in the general
population. Only patients suffering from important or unstable coronary heart disease or those at risk
for or having osteoporosis should be advised to take no caffeine or in small amounts (1 to 2 cups a
day). For persons with an anxiety disorder, a less clear recommendation can be made, because of a
lack of arguments for a causal relationship.
3.2. Nicotine
As discussed in the Introduction, the prevalence of use of nicotine is basically that of tobacco,
which makes nicotine the second most used psychostimulant. It is a natural alkaloid component found
in tobacco leaves. Each puff of cigarette contains about 50 micrograms of nicotine. Nicotine can be
absorbed through the lung and the gastro-intestinal system, but its absorption through the oral mucosa
has been shown to be the principal route of absorption for smokers who do not inhale and for
smokeless tobacco users [45].
The half-life of nicotine is two hours. Approximately 80 to 90% of nicotine is metabolized by the
lungs, liver and kidneys. Its principle metabolite cotinine, which has a half-life of 15 to 20 hours, is
active with stimulant properties. Approximately 17% of nicotine is excreted unchanged in the urine
and nicotine can be found in the milk of lactating women. The metabolism of nicotine explains a racial
difference in tobacco related disease. Black people have higher nicotine intake and slower cotinine
metabolism, accounting for more tobacco related diseases, even with the same daily intake of nicotine
[46]. An important variability exists in nicotine metabolism through the cytochrome P450-2A6
pathway, resulting in important differences in plasma nicotine and cotinine concentration, for people
taking a similar dose of nicotine. A few individuals have slow metabolism, but uncertainty exists about
a possible link with susceptibility to nicotine addiction [47]. The nicotinic receptor genes
polymorphism account for different nicotinic acetylcholine receptors and an important variability in
addictive potential for nicotine and smoking [48]. Nicotine is a hepatic enzymatic inductor and when
stopped, certain drugs can require a dosage reduction. These include acetaminophen, caffeine,
imipramine, oxazepam, pentazocine, propranolol and theophylline [49]. A decrease in circulating
catecholamines may warrant a decrease of dose of adrenergic antagonists such as prazosin and
labetalol, or an increase in dose of adrenergic substances such as isoproterenol and phenylehrine [50].
Pharmaceuticals 2010, 3
2338
An increase in insulin absorption also exists and may necessitate a dosage reduction to avoid
hypoglycemia.
Nicotine is a potent ganglionic and central nervous stimulant. It binds to nicotinic cholinergic
receptors that are located in the brain, autonomic ganglia, adrenal glands and at neuromuscular
junctions [49]. Nicotine induces a complex pattern of mixed sympathetic and parasympathetic
responses, but its resultant major effect is sympathetic neural stimulation. It can be central or
peripheral, including a catecholamine release from the adrenal glands and a direct release from
vascular nerve endings. It also enhances the release of the following neurotransmitters: epinephrine,
norepinephrine, dopamine, acetylcholine, serotonin, vasopressin, glutamate, nitric oxide, calcitonin
growth-related peptide and β-endorphin [51]. The highly addictive potential of nicotine has been
linked to its dopaminergic properties [52], and its rapid and short action. Nicotine improves cognitive
performances by improving learning, memory and attention.. These effects of nicotine have been
exploited in the treatment of neurodegenerative diseases, as for example in the treatment of
Alzheimer’s disease patients where nicotine has been shown to attenuate the decline of the attention
deficits symptomatic of this disease [53].
When considering health effects of nicotine, most studies concern smokers, so the independent
effects of nicotine and smoking cannot always be separated. In the following paragraphs we have tried
to separate both effects when possible. Nicotine increases cardiovascular risks by itself, without the
known negative effects of smoke. It transiently increases the blood pressure with approximately 5 to
10 mmHg [54] and the heart rate up with 10 to 15 beats per minute [55]. Despite the acute effect on the
arterial pressure, habitual smokers do not have higher blood pressure than nonsmokers [56]. It may be
related to the decreased body weight of nicotine users, and a vasodilator effect of cotinine [57]. The
cardiovascular risk is also increased by the coronary vasoconstriction and reduced coronary blood flow
[58]. From studies conducted with smokers, the effects of nicotine on the cerebral circulation are both
vasoconstriction and vasodilatation [59]. The vasoconstriction is partially due to thromboxane A2
release, the vasodilatation by the local formation of nitric oxide. Another deleterious effect of nicotine
is a hypercoagulable state, due to platelet activation and increased fibrinogen level [60-61]. All this has
a clinical importance because thrombosis is a major factor in vascular events in smokers [62].
Cigarette smoking increases the risk of myocardial infarction and sudden death more than angina
pectoris does. Nicotine seems to play a role in this pathophysiology [63]. After a coronary event,
smokers who continue to smoke after thrombolysis have a very high risk of reinfarction or reocclusion
[64]. The risk of continued smoking in a stented coronary lesion is less clear [65]. Another way the
cardiovascular damage is increased is through the endothelial dysfunction induced by nicotine or
smoke. Even without atherosclerosis smokers have a paradoxical response to acetylcholine, which
appears to result from impaired release of nitric oxide (NO) by the endothelium [66]. The vascular
protector roles of NO are vasodilatation, reduction in platelet aggregation, smooth muscle cell
proliferation, and monocytes adhesion to the endothelium.
The lipid metabolism is influenced by nicotine in the way that is largely unknown [67], but the
increased cardiovascular risk seems to be independent of this change [68]. Nicotine also contributes to
the development of insulin resistance. This have been suggested in a study of 40 non-obese middle-age
men, in whom long term use of nicotine-containing gums was associated with the onset of insulin
resistance and hyperinsulinemia [69].
Pharmaceuticals 2010, 3
2339
The cardiovascular safety of nicotine replacement for smokers willing to quit has been suggested
through the Lung Health Study cohort [70]. In this study on 5,887 middle-aged smokers with chronic
obstructive pulmonary disease, no difference in hospital admissions for cardiovascular events was
found between smokers and those who quit smoking with nicotine replacement. Two other controlled
trials of nicotine replacement also provided no evidence for an increase in coronary events in patient
with coronary disease [71-72].
Although there is no definite evidence that nicotine itself could induce cancer, several studies
suggest that nicotine might play a role as a carcinogen, independent of smoke. This has been supported
by the fact that nicotine promotes in vivo the growth of cancer cells and the proliferation of endothelial
cells [73]. Different studies reported that nicotine suppressed apoptosis induced by different stimuli
such as chemotherapeutic agents in Non Small Cell Lung Cancer treatment [74]. This explains maybe
why the efficacy of the treatment of a cancer can be diminished by nicotine.
The symptoms of nicotine withdrawal syndrome include irritability, depressed mood, restlessness,
anxiety, decreased concentration, increased hunger and eating, insomnia, and craving for tobacco [75].
Nicotine withdrawal in untreated smokers produces mood disturbances comparable in intensity to
those seen in depressed outpatients [76]. The withdrawal symptoms last for several weeks in the
majority of cases [77].
The treatment for nicotine addiction is principally based on psychological approaches, as for other
psychostimulants. The pharmacological means to enhance rate of success concerns the anti-depressant
bupropion [78] and the partial agonist α4β2 nicotinic acetylcholine receptors varenicline [79]. Clinical
trials have found that varenicline is superior to bupropion to quit smoking [80], and that prolonged
administration of varenicline reduces relapse in abstinent smokers for 12 weeks after initial therapy [81].
In summary, independent of risks related to smoking, nicotine itself has the potential to increase the
cardiovascular risk and decrease insulin resistance. Besides the advice to avoid tobacco smoke,
nicotine should be avoided after a vascular event and in diabetics. Even if there is a popular belief that
it is too late to stop smoking when a cancer has been diagnosed, the importance of smoking cessation
should be emphasized, to enhance the treatment efficacy. Psychological support and techniques
combined with pharmacologic treatment should be offered for nicotine addiction treatment.
3.3. Cocaine
Cocaine is the most used single illicit psychostimulant and probably the most dangerous one. It is
consumed by more than 14 million people worldwide, 0.3% of the adult population age 15 to 64 years
[82]. It is less available in Africa, Asia, Eastern Europe and Oceania where its consumption is
less frequent.
Cocaine is an ester alkaloid found in leaves of the Erythroxylon Coca plant. It growed typically in
the Andes Mountain in South America, where the traditional oral use of the leaves is not associated in
general with any negative consequences [83]. A German student, Albert Niemann, isolated the active
ingredient cocaine from the leaf in 1860. It then became a ingredient of many popular preparation as
coca wine or Coca-Cola, at a dose of 0.75 mg per 28 ml. Increasing reports of adverse effects as stroke
and cardiac arrest warranted its government controls and its removal from Coca-Cola in 1903.
Pharmaceuticals 2010, 3
2340
Examples of its street name are “C”, “Snow”, “Aspirin”, “Coke” or “White Lady” for the snorted
form, and “Crack”, “Base”, “Supercoke”, “Rock” or “Scotty” for the smoked form.
The typical pattern of use is in “binge” [84]. Shorts and intense periods of use are separated by
longer period of little use or abstinence. Situations occur where cocaine is used for an extended time
until the finances are exhausted or access to the substance is interrupted. The effect of cocaine is
mediated through enhancement of the monoamine neurotransmitter activity in the central and
peripheral nervous system. Cocaine blocks the reuptake of dopamine, norepinephrine and to a lesser
degree serotonine [85-86]. Its positive psychological effects and important abuse potential are
considered to be in relation to the enhancement of brain dopamine activity, dopamine being the main
neurotransmitter of the brain reward and learning system [87]. Cocaine has a unique second action: it
blocks voltage-gated membrane sodium ion channels and confers its anesthetic and arrhythmic
properties [88]. An important effect to be known is the potential of QT prolongation [89], which can be
deleterious for some patients, e.g. those with congenital long QT, or those on methadone substitution
or other medication prolonging the QT interval.
Cocaine can be found in two physical forms: a hydrochloride salt and a cocaine base rock. The first
is soluble in water and can be snorted or injected, its melting point is that hot (195°) that cocaine is
already destroyed if heated; the second has a low melting point (95°), making it possible to smoke. It
is difficult to solve into water and cannot be injected [90]. The average purity of cocaine is 50%, and it
is mixed with diluents including inert fillers resembling cocaine in appearance, or active chemicals that
can be toxic (e.g. benzene, acetone, lidocaine, procainamide, ephedrine, amphetamine, caffeine or
PCP) [91].
After absorption, cocaine is rapidly absorbed in the blood and taken to most body organs, including
the brain, heart, kidneys, adrenal glands and liver. Its crosses the placenta [92] and appears in breast
milk [93]. The onset of action is very fast for the smoked or injected form (within seconds) and a
couple of minute for the snorted form. The oral form, rarely observed, would take about 20 to
30 minutes to produce effects. The action lasts typically 15 to 30 minutes for the smoked or injected
form, about 1 hour for the snorted form, and 2 to 3 hours for the ingested one. Those kinetic
differences are thought to explain the different addiction potential of those forms, the injected or
smoked form presenting the greatest addiction potential [94]. The amount of cocaine taken has also
been linked to the risk of addiction. In general, the addictive potential is high and community-based
interview surveys show that up to one in six persons who use cocaine will become dependent [95].
Another study found in last year users, that dependence or abuse occurred in up to 25% of people [96].
Cocaine is metabolized by the liver mainly in inactive metabolites, the only active metabolite being
norcocaine. It accounts for only 5% of the metabolites but has a liver toxicity [97]. The special
situation of a new compound formed when cocaine is taken with alcohol has to be mentioned.
Cocaethylene has a longer half-life and is more cardiotoxic and toxic for the liver than cocaine or
alcohol alone [98].
The effects of cocaine are increased energy and sociability, euphoria, decreased fatigue, need for
sleep and appetite [99-100]. An intense pleasurable feeling has been described as a “total body
orgasm”, probably following smoked or injected cocaine. With increasing dose and duration of use, the
incidence of unintended adverse effect increases. They include dysphoric mood, panic attack, paranoid
reactions, impaired judgment and psychotic symptom as delusions and hallucinations. The incidence of
Pharmaceuticals 2010, 3
2341
insomnia, weight loss, paranoia or hallucination can be very high even in out of treatment cocaine
users, up to 40% of them [101]. Behavioral concurrent effects can be agitation, tremor, dyskinesia and
repetitive or stereotyped behaviors, as compulsive research of the substance [102]. Associated signs
are tachycardia, dilated pupils, sudation and nausea. Cocaine is often considered as aphrodisiac, but
under its effect, if sexual desire is possibly enhanced, erection can be impaired and ejaculation delayed
or inhibited [103].
The physical harms are mainly related to cardiovascular accidents and consequences of injection
and sharing equipment (e.g. blood borne viruses, abscess, endocarditis). Increased cardiac oxygen
demand, vasoconstriction and platelets activation are synergic in causing acute coronary syndromes
[104] or cerebral strokes [105], even in young healthy individuals. Cocaine use is found in 25% of
nonfatal heart attack in persons younger than 45 years [106]. It also increases the risk of cardiac
arrhythmias and sudden death [107]. The cerebrovascular bed is also concerned: a US study found a
14-fold increase in the risk of ischemic or haemorrhagic stroke among cocaine users compared with
matched controls (and a fourfold increased risk for methamphetamine) [108]. Other neurologic acute
events concerns seizures that can happen even at the first time of use and without prior history of
seizure [109].
The withdrawal syndrome is prominently psychological as with other psychostimulants. It consists
in fatigue, decreased ability to feel pleasure (anhedonia), anxiety, concentration difficulties, increased
appetite, sleep and dreaming. The physical signs may include musculoskeletal pain, tremor, chills, and
involuntary movements [110]. This withdrawal syndrome is not dangerous, except for a risk for
suicidal ideation in the initial period (which has been termed the “crash”) [111] and some myocardial
ischemia described in the first week of withdrawal [112].
The physical chronic consequences are less important than the acute ones. Cardiomyopathy and
myocarditis have been described [113]. Aggravation of an underlying hypertension may occur with
enhanced renal disease [114]. Chronic cocaine snoring can cause the classic nasal septum perforation,
oropharyngeal ulcers and osteolytic sinusitis [115]. If smoked, it can cause a moderately decreased
pulmonary diffusion capacity, the spirometric tests being unchanged. The gastrointestinal chronic
consequences are mainly gastric and duodenal ulcers [115].
More important are the neuropsychiatric long term consequences. Cocaine has been shown to be
neurotoxic for the dopamine neurons, especially in the midbrain [116]. Other neuroimaging studies
found cerebral gray matter atrophy, small cerebral perfusion defects and decreased D2 dopamine
receptors in the striatum [117]. The clinical significance of these abnormalities are not clear, but
cognitive impairment affecting visuo-motor performance, attention, verbal memory and risk-reward
decision-making has been described, lasting at least several weeks after cutting down the use of
cocaine [118].
The treatment of the intoxication consists principally of the symptomatic treatment of the
underlying process. Benzodiazepines are useful to treat agitation and cardiovascular toxicity, as can be
phentolamine to alleviate the vasoconstriction and hypertension due to sympathetic activation.
β-Blockers have to be avoided as they can worsen the vasoconstriction due to unbalanced α stimulation
[119]. One retrospective cohort study found a benefice for β-blockers, but methodological problems
does not allow real conclusion [120]. α/β-blockers (e.g. labetalol) should also be avoided because of a
Pharmaceuticals 2010, 3
2342
lack of efficacy on the vasospasm [121]. Depression persisting more than two or three weeks could
warrant an antidepressant therapy [122].
The mainstay treatment of cocaine addiction is psychosocial, with basically no approach being
proved to be superior to the other [123]. Nevertheless, treatment intensity and treatment lasting a
minimum three months has been associated with better outcomes [124]. Long term abstinence rates are
typically under 50%. Involvement of peer self-help groups (e.g. Cocaine Anonymous, Narcotics
Anonymous) seems to improve treatment outcomes [125]. No medication is proven to be an efficient
treatment for cocaine dependence nor have any been labelled for this indication, but several molecules
have shown some efficacy, for example topiramate (200 mg daily) [126] and tiagabine (12 or 24 mg
daily) [127]. Preliminary findings suggest that GABA-b receptor agonist baclofen [128], the
antidepressant citalopram [129], and the serotonin (5-HT3) receptor antagonist odansetron may
diminish cocaine use in selected patients. Some other trials suggest that substitution with long lasting
oral stimulants such as amphetamine might be effective [130]. The possible additive cardiovascular
toxicity if the patient relapses is a problem in this setting [131]. Finally, some interesting future
solutions currently under investigation include N-acetylcysteine (which interferes with glutamate brain
activity) [132], an anti-cocaine vaccine [133] and disulfiram, possibly acting by another mechanism
than that involved in the decrease of alcohol intake (probably through dopamine β-hydroxylase
inhibition) [134].
In summary, cocaine is certainly one of the most dangerous and addictive psychostimulants (along
with methamphetamine). Its toxicity is poorly correlated with its dosage or route of administration
[135], but its addiction potential is more important if smoked or injected. Severe acute adverse effects
are primarily cardiovascular (myocardial infarction, sudden death by arrhythmia), neurologic (stroke,
seizure) and psychiatric (panic attack, paranoia, suicide). The simultaneous consumption with alcohol
induces the formation of cocaethylene; with QT- prolonging medications it can prolong QT interval
even more and induce ventricular arrhythmias. Potential users have to be warned about the risks of
cocaine in general and in particular in its smoked or injected form, or if taken with alcohol, methadone
or other substances susceptible to alter cardiac conduction.
3.4. Methylenedioxymethamphetamine (MDMA, ecstasy) and derivatives (MDA, MDEA, PMA)
These substances are designer drugs that are classified as psychostimulants and hallucinogens.
Nevertheless, MDMA’s hallucinogenic properties are light and normally limited to visual disturbances
[136]. MDMA is one of the most commonly used synthetic drugs today. Its street names include “E”,
“Adam”, “Clarity”, “Stacy”, “lover speed” and “essence”. After its synthesis in 1914 as a potential
appetite suppressant, it was used in psychotherapy, but abandoned because of its side-effects. In the
late 1980s, it became popular as a recreational drug, and prevalence of use increased in teenagers and
young adults attending “rave” dance parties, night clubs and rock concerts. The prevalence of use in
the last 12 months among university students has been reported to be as high as 13 to 39% in the
United States and the United Kingdom [137-138], whereas the percentage of adults who have been
taking MDMA in last year seems to be between 0.8 and 3.7%. Ecstasy is mainly sold in the form of
pills or tablets, but may be found in powder that can be snorted or smoked. Each tablet typically
contains 50 to 200 mg of active substance and is sold for about 8 to 15 Euros (11 to 21 $US).
Pharmaceuticals 2010, 3
2343
The chemical structure of MDMA has analogies with both mescaline and methamphetamine. The
drug has central stimulant and psychedelic effects mediated by serotonin (5-HT), and to a lesser
proportion by dopamine [139-140]. Serotonin is thought to play a role in mood, appetite regulation and
body temperature regulation. MDMA causes serotonin release, blocks its reuptake, and blocks its
synthesis. The intraneuronal 5-HT stores are depleted, and the 5-HT concentration in the synaptic cleft
is increased. The effect typically begins within the first hour, and lasts for 3 to 6 hours [141]. Other
chemically close substances can be found mixed with MDMA in the preparations. These include MDA
(methylenedioxyamphetamine), known as “love pill” because of intense euphoria and entactogen
effect, MDEA (methylenedioxyethamphetamine) a substance very similar to MDMA, and PMA
(paramethoxyamphetamine), suspected to be more toxic that MDMA. In an Australian study, a high
proportion of persons needing emergency room admission for ecstasy intoxication actually had PMA
in their urine samples [142]. The clinical effects of MDMA include a feeling of euphoria together with
relaxation, empathy, and energy [143]. Sexual desire and satisfaction are enhanced [144]. The effects
may include impulsive or paranoid reactions. The sense of appetite and the need to sleep are
suppressed; still the feeling of thirst can sometimes be enhanced even without a water deficit after
MDMA use. This can lead to absorption of large quantities of water, leading to hyponatremia, cerebral
edema and even death [145]. Arousal of the body temperature as a direct consequence of serotonin
stimulation, facilitated by a hot environment and sustained physical activity (dancing), can cause
hyperthermia and dehydration followed by rhabdomyolysis, acute renal failure, disseminated
intravascular coagulation, liver and cerebral damages, and seizures [146-147]. Researchers in Australia
did a compilation of hyperthermia case reports (n=69) from MDMA and found a clear correlation of
the fatality rate and the body temperature at the arrival in the emergency room (20% for
temperature < or equal to 39.5°C, 78% for temperature > 42.5°C) [148]. The temperature increase was
shown to be longer if cannabis was used with MDMA and the heart rate was increased [149]. The
same team searched for other acute adverse reactions to MDMA and found in total ten cases of
seizures without hyperthermia, twelve cases of cerebrovascular accident, and six cases (all fatal) of
cardiac events. The cardiovascular events are certainly linked to the important cardiovascular
stimulation as described in a controlled study showing increased heart rate (by 28 beats per minute),
systolic blood pressure (by 25 mmHg), diastolic blood pressure (by 7 mmHg) and cardiac output (by 2
liters by minute) [150]. The Australian team also found 39 cases of liver injury without hyperthermia;
11 of these required liver transplantation, and six were fatal. There seems to be no clear correlation
between MDMA doses and severity of outcome [151].
In the week following use of MDMA, depression and low concentration and/or memory problems
are reported by users as being relatively common [152]. The risk of development of more severe
psychopathological problems exists, with 31 cases of psychiatric complications described in the
medical literature comprising episodes of depression, panic attacks, “flashbacks” and delusion. This
can occur even after one single take of MDMA [153], or more [154]. In 12 of these cases a history of
cannabis use was reported, and in eight a family or personal history of psychiatric disorder [155].
Long term toxicity of MDMA and derivatives involve principally the brain, with several studies
using cerebral imaging to prove persisting abnormalities in humans who have used even moderate
quantities of MDMA [156-157]. The consequences of those images involve an impairment in short-
Pharmaceuticals 2010, 3
2344
term memory function [158-159], but their long term functional consequences remain uncertain and
point the need for large scale epidemiological studies.
The treatment consists principally of symptomatic relief of consequences of MDMA use. In acute
hyperthermia, the body temperature must be promptly restored, and the sodium and fluid balance also.
Dantrolene, a muscle relaxant has been used to control body temperature [160]. Benzodiazepines can
be useful in case of anxiety, agitation or seizures.
It is rare that MDMA users need treatment for the use of the substance itself. The pattern of use is
mostly infrequent recreational use in specific contexts without abuse or dependence, nor any
consequent physical withdrawal syndrome [161]. Nevertheless, the problem may be more severe,
given that some may use MDMA more often and by injection rather than orally [162]. These groups
might need interventions such as classical motivational and cognitive behavioral approach as proposed
for cocaine addiction, but currently no specific recommendations for treatment of MDMA
misuse exist.
With regard to prescription of selective serotonin reuptake inhibitors (SSRIs), an interesting finding
is that concomitant use of SSRIs and ecstasy block the usual subjective effect of MDMA [163]. Still,
the risk of serotoninergic syndrome should be assessed before this pharmaceutical approach could be
widely considered.
From a harm reduction perspective users should be advised to drink isotonic beverages in adequate
quantity and to control their body temperature, by regularly leaving hot dance floors and taking breaks
in a cool environment. Users should avoid taking MDMA in combination with ritonavir, fluoxetine or
cannabis. Special attention should be taken to inform people with psychiatric or cardiovascular
problems or personal or familial history of these diseases that they should absolutely avoid any
MDMA use. In summary, MDMA is not a pure psychostimulant and has some hallucinogenic
properties. It seems to present a smaller addiction potential than cocaine or methamphetamine.
Nevertheless, acute potentially fatal reactions are described, as well as neuropsychiatric long term
consequences that need further evaluation. A very serious systematic review about the health effect of
recreational ecstasy has been published in 2010 [164].
3.5. Methamphetamine and amphetamine
These substances have been extensively discussed in the press because of its rising consumption in
the US in late 90s and currently in Asia, and because of its impressive health consequences. The
prevalence of annual use has declined between 2002 and 2005 [165] to 0.5% of the US adult
population, but the rate of dependence within the users seems to have doubled between 2002 and 2004,
passing from 10.6 to 22.3% [166]. As discussed in the introduction, the latter prevalence of use in
Europe seems to be comparable, but is much higher in some Asian countries. An especially high
prevalence has been described in homosexual men and is associated with a high risk of HIV
transmission [167].
The street names of methamphetamine are “Meth”, “Crystal Meth”, “Speed”, or “Ice”. It can be
easily manufactured from widely available pseudoephedrine, with a risk of explosion and burns for
careless producers [168]. The substance can be taken orally, smoked, snored, injected or inserted
rectally [169]. Its effect and high addictive potential can largely be compared to cocaine, but its half
Pharmaceuticals 2010, 3
2345
life is longer and about 12 hours [170]. It produces a rapid and pleasurable rush related to the release
of dopamine, norepinephrine and serotonin, followed by euphoria, heightened level of alertness, and
increased energy [171]. Increased libido and enhanced sexual pleasure also occur, followed by
increased sexual activity with high risk behavior [172]. Dependence was clearly related to the route of
administration: two-thirds of injectors were dependent, as were 58% of smokers of the substance,
lower levels of dependence were seen among intranasal (33%) and oral (22%) users [173].
Amphetamine is less potent that methamphetamine but shares basically the same properties and risk. It
will be detailed in the “Prescribed substance abuse” section below.
A long list of possible acute side effects is known, although their incidence is unclear.
Methamphetamine sold in the street may be contaminated with multiple byproducts, including lead and
α-benzylphenylamine [174]. The main acute side effects seem to be cardiovascular (myocardial
infarction, stroke). One study in an emergency department in California showed 33 admissions in two
years with acute chest pain and methamphetamine positive screening test [175], and 25% of these were
diagnosed with acute coronary syndrome. The other adverse events are those of the others
amphetamine derivatives (hyperthermia, rhabdomyolysis, acute renal failure, seizures) [176], with
fatalities described [177]. Psychiatric acute reactions include anxiety, insomnia, paranoia, and
psychosis.
Chronic use of methamphetamine can cause important neurological and psychiatric problems
caused by dopamine depletion (anxiety, motor slowing and psychosis), as well as serotonin depletion
[178] (depression and memory loss). As physical consequences, cardiomyopathy and hepatitis have
been described [170]. A very typical physical appearance (“aging effect”) has been described with
chronic methamphetamine use and consists of a mix of malnutrition, severe dental decay and
poor hygiene.
The treatments do not differ from those for ecstasy (please refer to this substance), even if the
addictive behavior could be more prominent. Treatments are mainly supportive and centered on the
underlying anomaly in acute settings, and behavioral in the long term. A particular attention should be
given to suicidal ideation, as the withdrawal from methamphetamine is associated with a particularly
severe and prolonged depression, even more than the one of cocaine. A Cochrane review showed that
fluoxetine might have modest benefit in reducing short-term methamphetamine craving, but is of
limited interest since it did not permit a reduction in methamphetamine use [179]. In that paper, it is
stated that imipramine can help in maintaining people in therapy. Another promising substance could
be bupropion who permitted a decreased subjective methamphetamine-induced effect and craving, but
in laboratory setting [180].
3.6. Khat
The Khat plant (Celastraceus edulis; Catha edulis) is a flowering perennial green tree or large
shrub. It is primarily found in East Africa (Ethiopia, Kenya) and the Southwestern part of the Arabian
Peninsula, and grows wild at altitudes between 1,500-2,000 m. above sea level, usually reaching
6–7 m in height [181].
Pharmaceuticals 2010, 3
2346
The three main psychoactive ingredients of Khat leaves are alkaloids: S-(-)-cathinone (S-α-aminopropriophenone), norpseudoephedrine (cathine) and norephedrine, which are phenylpropylamines.
They can be considered psychostimulants structurally similar to amphetamine and noradrenaline [182].
Khat consumers use the fresh leaves since cathinone is relatively unstable and oxidizes at room
temperature. If left unrefrigerated for 48 hours, the leaves will contain only cathine. The leaves are
chewed; the cathinone is absorbed through the oral mucosa. After ingestion, the maximal plasma
concentrations of cathinone are attained after 1.5-3.5 hours [183]. The elimination half-life is around
four hours [184]. Cathinone, like amphetamines, induces the release of catecholamines from
presynaptic storage sites.
Worldwide it has been estimated that there are over 10 million khat users [181,185]. Khat is
mostly used in Somalia, Yemen, Kenya and Ethiopia in Muslim communities where alcohol use is
prohibited and khat use legal. Different surveys suggest that in these countries life-time prevalence of
khat use can be up to 80%, with prevalence of current use between 20 to 60%, and current daily use
between 17 and 30% [181,185]. Most of the surveys focus on frequency of use only and not on the
amount nor on negative consequences of khat use, so do not allow any conclusions on prevalence of
problematic khat use. Factors that have been found to be related to daily khat use are: male gender,
Muslim religion, smoking, higher level of education and family functioning. In fact, in many settings
khat is used in groups, and can be considered a gathering of social significance. Special khat sessions
can be organized at the occasion of festivities, sometimes in special rooms, with specific rituals and
with social rules to be respected, so the function of khat use is often more social and a medium to
exchange information than the search for the individual stimulant effect. In this sense, khat can be
considered to have the social role of alcohol as known in many non-Muslim countries. Women do have
their own sessions, but less frequently. Emigrants from the countries described seem to continue use of
khat after emigration, with increased risk of legal problems [186-187].
In clinical experiments in healthy human volunteers khat use induces subjective and objective
stimulant-like effects like increased energy, mental alertness and self-esteem. Subjects under effect of
khat have been described to have increased respiratory rate, body temperature, diastolic and systolic
blood pressure and heart rate, as well as mydriasis and dry mouth [187]. Chronic use can lead to
insomnia, anorexia, dysphoria, concentration difficulties [181]. Khat-induced psychoses have been
described in several case reports, mostly after “binge” use, and often disappear after a few days
cessation of drug use, if necessary combined with an antipsychotic [181]. It is to be noted that most of
these case reports concern emigrants from the khat using countries, who use khat in a “new” setting.
This might suggest an increased psychotogenic risk if khat is taken in an unfamiliar setting, but also be
due to publication bias.
Withdrawal symptoms that may occur after prolonged khat use have been described but seem to be
usually mild. They consist of lethargy, mild depression, slight trembling, and possibly recurrent
nightmares [188].
Other medical problems related to khat use that are described include: gastritis (maybe related to
the high tannin concentration), delayed gastric emptying and constipation (related to the
sympathomimetic effect of the Khat alkaloid) [181]. Effect on periodontal status is not clear, although
prevalence of the presence of oral keratotic white lesions in the oral cavity, especially at the side where
khat is used, seems to be increased [189]. There might be an increased risk of mouth and larynx cancer
Pharmaceuticals 2010, 3
2347
but available data are conflicting. Animal and human studies suggest that khat negatively influences
semen count, mobility and quality. Women who take khat during pregnancy have an increased risk of
dysmature infants, not of congenital malformations or stillbirth [190]. In breastfeeding women
nor-pseudoephedrine can be found in breast-milk.
Although khat increases diastolic and systolic blood pressure, until at least one hour after ending a
session, this effect seems more pronounced in non-tolerant subjects. Habitual users may develop
tolerance to this sympathomimetic effects of khat. A few studies suggest an increased risk for acute
myocardial infarction in the hours after khat use [181]. Other medical problems might be related to the
presence of pesticides, fungi or parasites in the khat leaves [181]. With regard to treatment of khat
misuse or dependence, two case reports (three cases) propose bromocriptine during the withdrawal
phase (one case was treated for four weeks) [191-192].
In summary, khat use is an integrated and socially accepted, probably in general unproblematic,
habit in a few Asian and African Muslim countries. As for other psycho-active substances, khat use
covers the spectrum of beneficial to non-problematic use, problematic use and dependence, but criteria
for, and data on the prevalence of these levels of use are lacking. Most epidemiological studies
consider only the frequency of use and not the amount of substance, so recommendations of a safe
level of use are lacking. Khat dependence is associated with increased morbidity and societal and
economical costs. With regard to treatment, although bromocriptine prescription might have some
interest there are no controlled trials available, and no specific treatment options can be recommended.
We can expect standard motivational and psychological interventions in addiction medicine to have
their place here too
3.7. Prescribed substance abuse
The definition of prescribed substance abuse is the use of a recognized medication, usually by
self-administration, in a manner that differs from medical, legal and social standards, usually by
self-administration. This issue is of great interest because of its prevalence, especially concerning pain
killers, opiates, sedatives and hypnotics. Diverted psychostimulant use seems to be less frequent.
Nevertheless, when all medications are considered together, it is estimated by the Drug Enforcement
Administration in the USA that the street value of diverted controlled medication rivals the annual
street value of cocaine. The abuse of prescription drugs has risen globally, both in the US [193] and
worldwide [194]. The wide availability of controlled medications for sale on the Internet also favors
this trend [195]. The factors contributing to this rise are a misperception of pharmaceutical drugs as
being safe, their relatively low cost, and wide availability [195].
This problem concerns the persons using diverted medication, but paradoxically also physicians
who undertreat certain diseases because of their reluctance to prescribe medication with abuse
potential. This phenomenon has been described for anxiety disorder, attention deficit/hyperactivity
disorder (ADHD) and chronic pain [196].
There are criteria to help to differentiate prescription drug abuse and addiction from physical
dependence on psychoactive drugs without addiction. The latter can occur within the context of good
medical care (e.g. opioid dependence in chronic pain treatment without addiction). These five criteria
are [197]:
Pharmaceuticals 2010, 3
•
•
•
•
•
2348
Intent (a medication is taken to treat a diagnosed illness);
Consequences (the goal and effect of a treatment are to improve the quality of life);
Control (a treatment is controlled cooperatively by the patient and his/her physician);
Legality;
Pattern (medical drug use is stable).
For the vast majority of patients with prescription drug abuse or addiction, the onset of their
addictive problem precedes the initiation of prescribed controlled drugs [198]. This should help
physicians to recognize most of the patients requiring particular attention with prescription. Prescribed
psychostimulants susceptible to be abused are:
Amphetamines (including methylphenidate), prescribed for ADHD and daytime sleepiness in
narcolepsy or sleep apnea syndrome. The adult dosage is usually about 20 mg per day, but recent
studies showed efficacy for higher dosage, up to 70 mg per day [199]. In controlled clinical trials,
amphetamine treatment allows clinically significant amelioration between 55 to 70% of patients for
ADHD, and 65-85% for narcolepsy. Methylphenidate is an amphetamine like stimulant
(a phenylethylamine) and catecholamine reuptake inhibitor. It is less efficient that amphetamine in
narcolepsy (70% improvement of daytime wakefulness versus 80%) [200]. The safety of those
treatments is not described in controlled studies and referral to the knowledge related to illicit use is
necessary.
Methamphetamine, prescribed in the USA, but not in Europe, for ADHD and obesity. The habitual
dosage is 5 mg three times a day before meals for obesity, and up to 20 mg per day for ADHD. It has a
lower security profile, but probably similar effects compared to other medical stimulants such as
amphetamine, methylphenidate or modafinil, and its prescription should be carefully considered.
Modafinil is prescribed as an appetite suppressant or in sleep disorders, sibutramine as an appetite
suppressant. They are stimulant-like drugs that increase levels of monoamines, serotonin, noradrenalin
and dopamine. Many physicians prefer it over amphetamine, because it has less abuse potential and
probably less cardiovascular risks. Still, long-term risks and abuse potential are not well known.
The serotonin selective reuptake inhibitors and the other antidepressants, even if able to create
symptoms with sudden discontinuation [201], are not described to have an addictive potential. This
class of medications does not enhance dopamine levers and does not produce brain rewards [202]. In
summary, the prescribed psychostimulants are indicated principally, and maybe underused, for the
treatment of hyperactivity/attention deficit disorders in children, adolescent and adults. Paradoxically,
they are abused by an increasing number of people causing important individual and public health
problems. A way to recognize potential abusers is to inquire about previous addictive behavior.
4. Conclusions
The psychostimulants are by far the most used psychoactive and potentially addictive substances
used all over the World and include different legal and illegal substances with different addictive
potentials and health risks. They include substances that have essentially beneficial effects such as
Pharmaceuticals 2010, 3
2349
caffeine, but also some particularly dangerous substances, as cocaine and methamphetamine. Primary
care physicians are probably the cornerstone for the detection of people using psychostimulants
occasionally or chronically, often without any conscience of the danger linked to their behavior. They
are also in the best position to provide a non-judgmental counseling and brief intervention. Patients
who need more intense or specific intervention can be referred to substance abuse specialists.
Treatment of psychostimulant addiction is mostly psycho-social, few medications are available, and
treatment outcomes still need improvement.
References and Notes
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Flegal, K.M.; Carroll, M.D.; Ogden, C.L.; Johnson, C.L. Prevalence and trends in obesity among
US adults, 1999-2000. JAMA 2002, 288, 1723-1727.
Froehlich, T.E.; Lanphear, B.P.; Epstein, J.N.; Barbaresi, W.J.; Katusic, S.K.; Kahn, R.S.
Prevalence, recognition, and treatment of attention-deficit/hyperactivity disorder in a national
sample of US children. Arch. Pediatr. Adolesc. Med. 2007, 161, 857-864.
Kessler, R.C.; Adler, L.; Barkley, R.; Biederman, J.; Conners, C.K.; Demler, O.; Faraone, S.V.
Greenhill, L.L.; Howes, M.J.; Secnik, K.; et al. The prevalence and correlates of adult ADHD in
the United States: results from the National Comorbidity Survey Replication. Am. J. Psychiatry
2006, 163, 716–723.
Longstreth, W.T., Jr; Koepsell, T.D.; Ton, T.G.; Hendrickson, A.F.; van Belle, G. The
epidemiology of narcolepsy. Sleep 2007, 30, 13-26.
Knorr, U.; Kessing, L.V. The effect of selective serotonin reuptake inhibitors in healthy subjects.
A systematic review. Nord. J. Psychiatry 2010, 64, 153-163.
WHO Report on the Global Tobacco Epidemic, 2008—The MPOWER package,
http://www.who.int/tobacco/mpower/en/index.html/ accessed on 22 July 2010.
Observatoire européen des drogues et des toxicomanies. Rapport annuel 2009 — État du
phénomène de la drogue en Europe ; Luxembourg: Office des publications de l’Union
européenne , Lisbon, Portugal, 2009.
Proceedings of the Community Epidemiology Work Group. Epidemiologic Trends in Drug
Abuse. Advance Report and Highlights/Executive Summary: Abuse of Stimulants and Other
Drugs; U.S. Department of Health and Human Services, National Institutes of Health: Bethesda,
Maryland, USA, 2005; http://www.drugabuse.gov/PDF/CEWG/AdvReport_Vol1_105.pdf/,
accessed on 21 July 2010.
Degenhardt, L.; Chiu, W.-T.; Sampson, N.; Kessler, R.C.; Anthony, J.C.; Angermeyer, M.;
Bruffaerts, R.; de Girolamo, G.; Gureje, O.; Huang, Y.; et al. Toward a global view of alcohol,
tobacco, cannabis, and cocaine use: Findings from the WHO World Mental Health Surveys.
PLoS Med. 2008, 5, e141.
Pinto, E.; Pitchot, W.; Ansseau, M. Pychostimulants. Rev Med Liege 2008, 63, 411-416.
Corti, R.; Binggeli, C. ; Sudano, I. ; Spieker, L. ; Hänseler, E. ; Ruschitzka, F. ; Chaplin, WF.;
Lüscher, T.F. ; Noll, G. Coffee acutely increases sympathetic nerve activity and blood pressure
independently of caffeine content: role of habitual versus nonhabitual drinking. Circulation 2002,
106, 2935-2940.
Pharmaceuticals 2010, 3
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
2350
Harland, B.F. Caffeine and nutrition. Nutrition 2000, 16, 522-526.
Grigg, D. The worlds of tea and coffee: Patterns of consumption. Geo J. 2002, 57, 283-294.
Reissig, C.J.; Strain, E.C.; Griffiths, R.R. Caffeinated energy drinks-a growing problem. Drug
Alcohol Depend. 2009, 99, 1-10.
Cornelis, M.C.; El-Sohemy, A.; Kabagambe, E.K.; Campos, H. Coffee, CYP1A2 genotype, and
risk of myocardial infarction. JAMA 2006, 295, 1135-1141.
Fredholm, B.B.; Battig, K.; Holmen, J.; Nehlig, A.; Zvartau, E.E. Actions of caffeine in the brain
with special reference to factors that contribute to its widespread use. Pharmacol. Rev. 1999, 51,
83-133.
Smith, A. Effects of caffeine on human behavior. Food Chem. Toxicol. 2002, 40, 1243-1255.
Lorist, M.M.; Snel, J.; Kok, A.; Mulder, G. Influence of caffeine on selective attention in wellrested and fatigued subjects. Psychophysiology 1994, 31, 525-534.
Childs, E.; de Wit, H. Subjective, behavioral, and physiological effects of acute caffeine in light,
nondependent caffeine users. Psychopharmacology (Berl) 2006, 185, 514-523.
James, J.E.; Rogers, P.J. Effects of caffeine on performance and mood: withdrawal reversal is the
most plausible explanation. Psychopharmacology (Berl) 2005, 182, 1-8.
Goldstein, J.; Silberstein, S.D.; Saper, J.R.; Ryan, R.E. Jr.; Lipton, R.B. Acetaminophen, aspirin,
and caffeine in combination versus ibuprofen for acute migraine: results from a multicenter,
double-blind, randomized, parallel-group, single-dose, placebo-controlled study. Headache 2006,
46, 444-453.
Bigal, M.E.; Sheftell, F.D.; Rapoport, A.M.; Tepper, S.J.; Lipton, R.B. Chronic daily headache:
identification of factors associated with induction and transformation. Headache 2002, 42,
575-581.
Hernan, M.A.; Takkouche, B.; Caamano-Isorna, F.; Gestal-Otero, J.J. A meta-analysis of coffee
drinking, cigarette smoking, and the risk of Parkinson's disease. Ann. Neurol. 2002, 52, 276-284.
Arendash, G.W.; Schleif, W. ; Rezai-Zadeh, K.; Jackson, E.K.; Zacharia, L.C.; Cracchiolo, J.R.;
Shippy, D.; Tan, J. Caffeine protects Alzheimer's mice against cognitive impairment and reduces
brain [β]-amyloid production. Neuroscience 2006, 142, 941-952.
Cannon, M.E.; Cooke, C.T.; McCarthy, J.S. Caffeine-induced cardiac arrhythmia: an
unrecognised danger of healthfood products. Med. J. Aust. 2001, 174, 520-521.
De Vreede-Swagemakers, J.J.; Gorgels, A.P.; Weijenberg, M.P.; Dubois-Arbouw, W.I.;
Golombeck, B.; van Ree, J.W.; Knottnerus, A.; Wellens, H.J. Risk indicators for out-of-hospital
cardiac arrest in patients with coronary artery disease. J. Clin. Epidemiol. 1999, 52, 601-607.
Corti, R.; Binggeli, C.; Sudano, I.; Spieker, L.; Hänseler, E.; Ruschitzka, F.; Chaplin, W.F.;
Lüscher, T.F. ; Noll, G. Coffee acutely increases sympathetic nerve activity and blood pressure
independently of caffeine content: role of habitual versus nonhabitual drinking. Circulation 2002,
106, 2935-2940.
Arnlov, J.; Vessby, B.; Riserus, U. Coffee consumption and insulin sensitivity. JAMA 2004, 291,
1199-1201.
MacKenzie, T.; Comi, R.; Sluss, P.; Keisari, R.; Manwar, S.; Kim, J.; Larson, R.; Baron, J.A.
Metabolic and hormonal effects of caffeine: randomized, double-blind, placebo-controlled
crossover trial. Metabolism 2007, 56, 1694-1698.
Pharmaceuticals 2010, 3
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
2351
Agardh, E.E.; Carlsson, S.; Ahlbom, A.; Efendic, S.; Grill, V.; Hammar, N.; Hilding, A.;
Ostenson, C.G. Coffee consumption, type 2 diabetes and impaired glucose tolerance in Swedish
men and women. J. Intern. Med. 2004, 255, 645-652.
Williams, C.J.; Fargnoli, J.L.; Hwang, J.J.; van Dam, R.M.; Blackburn, G.L.; Hu, F.B.;
Mantzoros, CS. Coffee consumption is associated with higher plasma adiponectin concentrations
in women with or without type 2 diabetes: a prospective cohort study. Diabetes Care 2008, 31,
504-507.
Klatsky, A.L.; Morton, C.; Udaltsova, N.; Friedman, G.D. Coffee, cirrhosis, and transaminase
enzymes. Arch. Intern. Med. 2006, 166, 1190-1195.
Choi, H.K.; Willett, W.; Curhan, G. Coffee consumption and risk of incident gout in men: A
prospective study. Arthritis Rheum. 2007, 56, 2049-2055.
Burke, LM. Caffeine and sports performance. Appl. Physiol. Nutr. Metab. 2008, 33, 1319.
Lopez-Garcia, E. ; van Dam, R.M. ; Li, T.Y.; Rodriguez-Artalejo, F.; Hu, FB. The relationship of
coffee consumption with mortality. Ann. Intern. Med. 2008, 148, 904-914.
Boehm, K.; Borrelli, F.; Ernst, E.; Habacher, G.; Hung, S.K.; Milazzo, S.; Horneber, M. Green
tea (Camellia sinensis) for the prevention of cancer. Cochrane Database Syst. Rev. 2009,
CD005004.
Kanis, J.A.; Johnell, O.; Oden, A.; De Laet, C.; Jonsson, B.; Dawson, A. Ten-year risk of
osteoporotic fracture and the effect of risk factors on screening strategies. Bone 2002, 30,
251-258.
Cauley, J.A.; Hochberg, M.C.; Lui, L.Y.; Palermo, L; Ensrud, K.E.; Hillier, T.A.; Nevitt, M.C.;
Cummings, S.R. Long-term risk of incident vertebral fractures. JAMA 2007, 298, 2761-2767.
Uhde, T.W. Caffeine provocation of panic: a focus on biological mechanisms. In Neurobiology
of Panic Disorder; Ballenger, J.C., Ed.; Alan R. Liss Inc: New York, NY, USA, 1990;
pp. 219-242.
Bruce, M.; Scott, N.; Shine, P.; Lader, M. Anxiogenic effects of caffeine in patients with anxiety
disorders. Arch Gen. Psychiatry 1992, 49, 867-869.
Satel, S. Is caffeine addictive?--a review of the literature. Am. J. Drug Alcohol Abuse 2006, 32,
493-502.
Nehlig, A. Are we dependent upon coffee and caffeine? A review on human and animal data.
Neurosci. Biobehav. Rev. 1999, 23, 563-576.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Text
Revision, 4th ed.; American Psychiatric Association: Washington, DC, USA, 2000.
Juliano, L.M.; Griffiths, R.R. A critical review of caffeine withdrawal: empirical validation of
symptoms and signs, incidence, severity, and associated features. Psychopharmacology (Berl)
2004, 176, 1-29.
Schevelbein H.; Eberhardt, R.; Loeschenkohl, K.; Rahlfs, J.; Bedall, J.K. Absorption of nicotine
through the oral mucosa-measurement of nicotine concentration in the blood after application of
nicotine and total particulate matter. Agents Actions 1973, 3, 254-258.
Perez-Stable, E.J.; Herrera, B.; Jacob, P.; Benowitz, N.L. Nicotine metabolism and intake in
black and white smokers. JAMA 1998, 280, 152-156.
Pharmaceuticals 2010, 3
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
2352
Malaiyandi, V.; Sellers, E.M.; Tyndale, R.F. Implications of CYP2A6 genetic variation for
smoking behaviors and nicotine dependence. Clin. Pharmacol. Ther. 2005, 77, 145-158.
Saccone, N.L.; Saccone, S.F.; Hinrichs, A.L. ; Stitzel, J.A.; Duan, W.; Pergadia, M.L.; Agrawal,
A.; Breslau, N.; Grucza, R.A.; Hatsukami, D.; et al. Multiple distinct risk loci for nicotine
dependence identified by dense coverage of the complete family of nicotinic receptor subunit
(CHRN) genes. Am. J. Med. Genet. B Neuropsychiatr. Genet. 2009, 150B, 453-466.
Benowitz, N.L. Pharmacology of nicotine: addiction and therapeutics. Annu. Rev. Pharmacol.
Toxicol. 1996, 36, 597-613.
Benowitz, N.L.; Kuyt, F.; Jacob, P. Influence of nicotine on cardiovascular and hormonal effects
of cigarette smoking. Clin. Pharmacol. Ther. 1984, 36, 74-81.
Okamura, T.; Noboru, T. Mechanism underlying nicotine-induced relaxation in dog saphenous
arteries. Eur. J. Pharmacol. 1994, 263, 85-91.
Dani J.A. Roles of dopamine signaling in nicotine addiction. Mol. Psychiatry 2003, 8, 255–256.
Levin, E.D.; Rezvani, A.H. Nicotinic treatment for cognitive dysfunction. Curr. Drug. Targets
CNS Neurol. Disord. 2002, 4, 423–431.
Pickering, T.; Schwartz, J.E.; James, C.T. Ambulatory blood pressure monitoring for evaluating
the relationships between lifestyle, hypertension and cardiovascular risk. Clin. Exp. Pharmacol.
Physiol. 1995, 22, 226-231.
Kool, M.J.; Hoeks, A.P.; Struijker Boudier, J.A.; Reneman, R.S.; Van Bortel, L.M.. Short and
long-term effects of smoking on arterial wall properties in habitual smokers. J. Am. Coll.
Cardiol. 1993, 22, 1881-1886.
Mikkelsen, K.L.; Wiinberg, N.; Hoegholm, A.;Christensen, H.R.; Bang, L.E.; Nielsen, P.E.;
Svendsen, T.L.; Kampmann, J.P.; Madsen, N.H.; Bentzon, M.W. Smoking related to 24-h
ambulatory blood pressure and heart rate. A study in 352 normotensive Danish subjects. Am J
Hypertens. 1997, 10, 483-491.
Benowitz, N.L.; Sharp, D.S. Inverse relation between serum cotinine concentration and blood
pressure in cigarette smokers. Circulation 1989, 80, 1309-1312.
Quillen, J.E.; Rossen, J.D.; Oskarsson, H.J.; Minor, R.L., Jr.; Lopez, A.G.; Winniford, M.D.
Acute effect of cigarette smoking on the coronary circulation: Constriction of epicardial and
resistance vessels. J. Am. Coll. Cardiol. 1993, 22, 6426-47.
Iida, M.; Iida, H.; Dohi, S.; Takenaka, M.; Fujiwara, H. Mechanisms underlying cerebrovascular
effects of cigarette smoking in rats in vivo. Stroke 1998, 29, 1656-1665.
Kannel, W.B.; D'Agostino, R.B.; Belanger, A.J. Fibrinogen, cigarette smoking and the risk of
cardiovascular disease from the Framingham Study. Am. Heart J. 1987, 113, 1006-1010.
Meade, T.W.; Imeson, J.; Stirling, Y. Effects of changes in smoking and other characteristics on
clotting factors and the risk of ischemic heart disease. Lancet 1987, 2, 986-988.
Benowitz, N.L. The role of nicotine in smoking-related cardiovascular disease. Prev. Med. 1997,
26, 412-417.
Zidovetzki, R.; Chen, P.; Fisher, M.; Hofman, F.M. Nicotine increases plasminogen activator
inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway.
Stroke 1999, 30, 651-655.
Pharmaceuticals 2010, 3
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
2353
Rivers, J.T.; White, H.D.; Cross, D.B.; Williams, B.F.; Norris, R.M.. Reinfarction after
thrombolytic therapy for acute myocardial infarction followed by conservative management:
Incidence and effect of smoking. J. Am. Coll. Cardiol. 1990, 16, 340-348.
Pell, J.P. Does smoking cessation reduce the risk of restenosis following coronary angioplasty?
Heart 2000, 84, 233–234.
Kiowski, W.; Linder, L.; Stoschitzky, K.; Pfisterer, M.; Burckhardt, D.; Burkart, F.; Bühler F.R..
Diminished vascular response to inhibition of endothelium-derived nitric oxide and enhanced
vasoconstriction to exogenously administered endothelin-1 in clinically healthy smokers.
Circulation 1994, 90, 27-34.
Mjos, O.D. Lipid effects of smoking. Am. Heart J. 1988, 115, 272-275.
Criqui, M.H.; Cowan, L.D.; Tyroler, H.A. ; Bangdiwala, S.; Heiss, G.; Wallace, R.B.; Cohn, R.
Lipoproteins as mediators for the effects of alcohol consumption and cigarette smoking on
cardiovascular mortality: Results from the Lipid Research Clinic Follow-up Study. Am. J.
Epidemiol. 1987, 126, 629-637.
Eliasson, B.; Taskinen, M.R.; Smith U. Long-term use of nicotine gum is associated with
hyperinsulinemia and insulin resistance. Circulation 1996, 94, 878-881.
Murray, R.P.; Bailey, W.C.; Daniels K.; Bjornson, W.M.; Kurnow, K.; Connett, J.E.; Nides,
M.A.; Kiley, J.P. Safety of nicotine polacrilex gum used by 3,094 participants in the Lung Health
Study. Chest 1996, 109, 438-445.
Joseph, A.M.; Norman, S.M.; Ferry, L.H.; Prochazka, A.V.; Westman, E.C.; Steele, B.G.;
Sherman, S.E.; Cleveland, M.; Antonuccio, D.O.; Hartman, N.; McGovern, P.G. The safety of
transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N. Engl. J.
Med. 1996, 335, 1792-1798.
Kimmel, S.E.; Berlin, J.A.; Miles, C.; Jaskowiak, J.; Carson, J.L.; Strom, B.L. Risk of acute first
myocardial infarction and use of nicotine patches in a general population. J. Am. Coll. Cardiol.
2001, 37, 1297-1302.
Catassi, A.; Servent, D.; Paleari, L.; Cesario, A.; Russo P. Multiple roles of nicotine on cell
proliferation and inhibition of apoptosis: Implications on lung carcinogenesis. Mutat. Res. 2008,
659, 221–231.
Dasgupta, P.; Kinkade, R.; Joshi, B.; Decook, C.; Haura, E.; Chellappan, S. Nicotine inhibits
apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and surviving. Proc. Natl.
Acad. Sci. USA 2006, 103, 6332–6337.
Hughes, J.R.; Hatsukami, D. Signs and symptoms of tobacco withdrawal. Arch. Gen. Psychiatry
1986, 43(3), 289–294.
Hughes, J.R. Clinical significance of tobacco withdrawal. Nicotine Tob. Res. 2006, 8, 153–156.
Patten, C.A.; Martin, JE. Measuring tobacco withdrawal: a review of self-report questionnaires.
J. Subst. Abuse 1996, 8(1), 93-113.
Wilkes, S. The use of bupropion SR in cigarette smoking cessation. Int. J. Chron. Obstruct.
Pulmon. Dis. 2008, 3(1), 45-53.
Coe, J.W.; Brooks, P.R.; Vetelino, M.G.; Wirtz, M.C.; Arnold, E.P.; Wirtz, M.C.; Arnold, E.P.;
Huang, J.; Sands, S.B.; Davis, T.I.; Lebel, L.A.; Fox, CB; et al. Varenicline: an α4β2 nicotinic
receptor partial agonist for smoking cessation. J. Med. Chem. 2005, 48, 3474–3477.
Pharmaceuticals 2010, 3
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
2354
Gonzales, D.; Rennard, S.I.; Nides, M.; Oncken, C.; Azoulay, S.; Oncken, C.; Azoulay, S.;
Billing, C.B.; Watsky, E.J.; Gong, J.; Williams, K.E.; Reeves, K.R. Varenicline, an α4β2
nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for
smoking cessation: a randomized controlled trial. JAMA 2006, 296, 47–55.
Tonstad, S.; Tonnesen, P.; Hajek, P.; Williams, K.E.; Billing, C.B.; Reeves, K.R. Effect of
maintenance therapy with varenicline on smoking cessation: a randomized controlled trial. JAMA
2006, 296, 64–71.
World Drug Report 2007. Report no. E.07.XI.5; United Nations Office on Drugs and Crime:
Vienna, Austria, 2007; http://www.unodc.org/documents/data-and-analysis/WDR-2007.pdf,
accessed on 21 July 2010.
Montoya, I.D.; Chilcoat, H.D. Epidemiology of coca derivatives use in the Andean region: a tale
of five countries. Subst. Use Misuse 1996, 31, 1227-1240.
Myers, M.G.; Rohsenow, D.J.; Monti, P.M.; Dey, A. Patterns of cocaine use among individuals
in substance abuse treatment. Am. J. Drug Alcohol Abuse 1995, 21, 223-231.
Rothman, R.B.; Baumann, M.H.; Dersch, C.M. et al. Amphetamine-type central nervous system
stimulants release norepinephrine more potently than they release dopamine and serotonin.
Synapse 2001, 39, 32-41.
Howell, L.L.; Kimmel, H.L. Monoamine transporters and psychostimulant addiction. Biochem.
Pharmacol. 2008, 75, 196-217.
Dackis, C.A.; O'Brien, C.P. Cocaine dependence: a disease of the brain's reward centers. J. Subst.
Abuse Treat. 2001, 21, 111-117.
Tisdale, J.E.; Shimoyama, H.; Sabbah, H.N.; Webb, C.R. The effect of cocaine on Ventricular
fibrillation threshold in the normal canine heart. Pharmacotherapy 1996, 16, 429-437.
Magnano, A.R.; Talathoti, N.B.; Hallur, R.; Jurus, D.T.; Dizon, J.; Holleran, S.; Bloomfield,
D.M.; Collins, E.; Garan, H. Effect of acute cocaine administration on the QTc interval of
habitual users. Am. J. Cardiol. 2006, 97, 1244-1246.
Hatsukami, D.K.; Fischman, M.W. Crack cocaine and cocaine hydrochloride. Are the differences
myth or reality? JAMA 1996, 276, 1580-1588.
Shesser, R.; Jotte, R.; Olshaker, J. The contribution of impurities to the acute morbidity of illegal
drug use. Am. J. Emerg. Med. 1991, 9, 336-342.
Ostrea, E.M., Jr. Testing for exposure to illicit drugs and other agents in the neonate: a review of
laboratory methods and the role of meconium analysis. Curr. Probl. Pediatr. 1999, 29, 37-56.
American Academy of Pediatrics Committee on Drugs. Transfer of drugs and other chemicals
into human milk. Pediatrics 2001, 108, 776-789.
Gossop, M.; Griffiths, P.; Powis, B.; Strang, J. Cocaine: patterns of use, route of administration,
and severity of dependence. Br. J. Psychiatry 1994, 164, 660-664.
Anthony, J.C.; Warner, L.A.; Kessler, R.C. Comparative epidemiology of dependence on
tobacco, alcohol, controlled substances, and inhalants: Basic findings from the National
Comorbidity
Survey.
Exp.
Clin.
Psychopharmacol.
1994,
2,
244-268;
http://www.umbrellasociety.ca/web/files/u1/Comp_epidemiology_addiction.pdf/, accessed on 21
July 2010.
Pharmaceuticals 2010, 3
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
110.
111.
112.
2355
Results from the 2006 National Survey on Drug Use and Health, National Findings; Report no.
SMA 07-4293; Office of Applied Studies, Substance Abuse and Mental Health Services
Administration: Rockville, MD, USA, 2005.
Warner, A.; Norman, A.B. Mechanisms of cocaine hydrolysis and metabolism in vitro and in
vivo: a clarification. Ther. Drug Monit. 2000, 22, 266-270.
Pennings, E.J.; Leccese, A.P.; Wolff, F.A. Effects of concurrent use of alcohol and cocaine.
Addiction 2002, 97, 773-783.
Angrist, B. Clinical effects of central nervous system stimulants: A selective update. In Brain
Reward Systems and Abuse; Engel, J., Oreland, L., Ingvar, D.H., Eds.; Raven Press: New York,
NY, USA, 1987; pp. 109-127.
Fischman, M.W.; Foltin, R.W. Cocaine self-administration research: implications for rational
pharmacotherapy. In Behavior, Pharmacology, and Clinical Applications; Higgins, S.T., Katz,
J.L., Eds.; Cocaine Abuse Academic Press: San Diego, CA, USA, 1998; pp. 181-207.
Williamson, S.; Gossop, M.; Powis, B.; Griffiths, P.; Fountain, J.; Strang, J. Adverse effects of
stimulant drugs in a community sample of drug users. Drug Alcohol Depend. 1997, 44, 87-94.
Rosse, R.B.; Fay-McCarthy, M.; Collins, J.P., Jr.; Risher-Flowers D, Alim TN, Deutsch SI..
Transient compulsive foraging behavior associated with crack cocaine use. Am. J. Psychiatry
1993, 150, 155-156.
Palha, A.P.; Esteves, M. Drugs of abuse and sexual functioning. Adv. Psychosom. Med. 2008, 29,
131-149.
Luis, A.; Tamam, M.; Deepak, T. Crack Whips the Heart: A Review of the Cardiovascular
Toxicity of Cocaine. Am. J. Cardiol. 2007, 100, 1040 –1043.
Neiman, J.; Haapaniemi, H.M.; Hillbom, M. Neurological complications of drug abuse:
pathophysiological mechanisms. Eur. J. Neurol. 2000, 7, 595-606.
Qureshi, A.I.; Suri, F.K.; Guterman, LR.; Hopkins, LN. Cocaine use and the likelihood of
nonfatal myocardial infarction and stroke. Circulation 2001, 103, 502-506.
Lange, R.A.; Hillis, L.D. Cardiovascular complications of cocaine use. N. Engl. J. Med. 2001,
345, 351-358.
Petitti, D.B.; Sidney, S.; Quesenberry, C.; Bernstein A. Stroke and cocaine or amphetamine use.
Epidemiology 1998, 9, 596–600.
Brust, J.C. Acute neurologic complications of drug and alcohol abuse. Neurol. Clin. 1998, 16,
503-513.
Khantzian, E.J.; McKenna, G.J. Acute toxic and withdrawal reactions associated with drug use
and abuse. Ann. Intern. Med. 1979, 90, 361-372.
Coffey, S.F.; Dansky, B.S.; Carrigan, M.H.; Brady, K.T. Acute and protracted cocaine abstinence
in an outpatient population: a prospective study of mood, sleep and withdrawal symptoms. Drug
Alcohol Depend. 2000, 59, 277-286.
Nademanee, K.; Gorelick, D.A.; Josephson, M.A.; Ryan M.A.; Wilkins, J.N.; Robertson, H.A.;
Mody, F.V.; Intarachot, V. Myocardial ischemia during cocaine withdrawal. Ann. Intern. Med.
1989, 111, 876-880.
Pharmaceuticals 2010, 3
2356
113. Bertolet, B.D.; Freund, G.; Martin, C.A.; Perchalski, D.L.; Williams, C.M.; Pepine C.J.
Unrecognized left ventricular dysfunction in an apparently healthy cocaine abuse population.
Clin. Cardiol. 1990, 13, 323–328.
114. Norris, K.C.; Thornhill-Joynes, M.; Robinson, C.; Strickland, T.; Alperson, B.L.; Witana, S.C.;
Ward, H.J. Cocaine use, hypertension, and end-stage renal disease. Am. J. Kidney Dis. 2001, 38,
523-528.
115. Boghdadi, M.S.; Henning, R.J. Cocaine: Pathophysiology and clinical toxicology. Heart Lung
1997, 26, 466-483.
116. Little, K.Y.; Ramssen, E.; Welchko, R.; Volberg, V.; Roland, C.J.; Cassin, B. Decreased brain
dopamine cell numbers in human cocaine users. Psychiatry Res. 2009, 168, 173-180.
117. Rojas, R.; Riascos, R.; Vargas, D.; Cuellar, H.; Borne, J. Neuroimaging in drug and substance
abuse part I: cocaine, cannabis, and ecstasy. Top Magn. Reson. Imaging 2005, 16, 231-238.
118. Rogers, R.D.; Robbins, T.W. Investigating the neurocognitive deficits associated with chronic
drug misuse. Curr. Opin. Neurobiol. 2001, 11, 250-257.
119. Lange, R.A.; Cigarroa, R.G.; Flores, E.D.; McBride, W.; Kim, A.S.; Wells, P.J.; Bedotto, J.B.;
Danziger, R.S.; Hillis, L.D. Potentiation of cocaine-induced coronary vasoconstriction by βadrenergic blockade. Ann. Intern. Med. 1990, 112, 897–903.
120. Dattilo, P.B.; Hailpern, S.M.; Fearon, K.; Sohal, D.; Nordin C. β-blockers are associated with
reduced risk of myocardial infarction after cocaine use. Ann. Emerg. Med. 2008, 51(2), 117-125.
121. Boehrer, J.D.; Moliterno, D.J.; Willard, J.E.; Hillis, L.D.; Lange, R.A. Influence of labetalol on
cocaine-induced coronary vasoconstriction in humans. Am. J. Med. 1993, 94, 608–610.
122. Schuckit, M.A. Drug and Alcohol Abuse. A Clinical Guide to Diagnosis and Treatment, 6th ed.;
Springer: New York, NY, USA, 2006.
123. Carroll, K.M. Recent advances in the psychotherapy of addictive disorders. Curr. Psychiatry
Rep. 2005, 7, 329-336.
124. Zhang, Z.; Friedmann, P.D.; Gerstein, D.R. Does retention matter? Treatment duration and
improvement in drug use. Addiction 2003, 98, 673-684.
125. Weiss, R.D.; Griffin, M.L.; Gallop, R.J.; Najavits, L.M; Frank, A.; Crits-Christoph, P.; Thase,
M.E.; Blaine, J.; Gastfriend, D.R.; Daley, D.; et al. The effect of 12-step self-help group
attendance and participation on drug use outcomes among cocaine-dependent patients. Drug
Alcohol Depend. 2005, 77, 177-184.
126. Kampman, K.M.; Pettinati, H.; Lynch, K.G.; Dackis, C.; Sparkman, T.; Weigley, C.; O'Brien,
C.P. A pilot trial of topiramate for the treatment of cocaine dependence. Drug Alcohol Depend.
2004, 75, 233-240.
127. Gonzalez, G.; Desai, R.; Sofuoglu, M.; Poling, J.; Oliveto, A.; Gonsai, K.; Kosten, T.R.. Clinical
efficacy of gabapentin versus tiagabine for reducing cocaine use among cocaine dependent
methadone-treated patients. Drug Alcohol Depend. 2007, 87, 1-9.
128. Shoptaw, S.; Yang, X.; Rotheram-Fuller, E.J.; Hsieh, Y.C.; Kintaudi, P.C.; Charuvastra, V.C.;
Ling, W. Randomized placebo-controlled trial of baclofen for cocaine dependence: preliminary
effects for individuals with chronic patterns of cocaine use. J. Clin. Psychiatry 2003, 64,
1440-1448.
Pharmaceuticals 2010, 3
2357
129. Moeller, F.G.; Schmitz, J.M.; Steinberg, J.L.; Green, C.M.; Reist, C.; Lai, L.Y.; Swann, A.C.;
Grabowski, J. Citalopram combined with behavioral therapy reduces cocaine use: a double-blind,
placebo-controlled trial. Am. J. Drug Alcohol Abuse 2007, 33, 367-378.
130. Shearer, J. The principles of agonist pharmacotherapy for psychostimulant dependence. Drug
Alcohol Rev. 2008, 27, 301-308.
131. Rush, C.R.; Stoops, W.W.; Hays, L.R. Cocaine effects during D-amphetamine maintenance: a
human laboratory analysis of safety, tolerability and efficacy. Drug Alcohol Depend. 2009, 99,
261-271.
132. Mardikian, P.N.; LaRowe, S.D.; Hedden, S.; Kalivas, P.W.; Malcolm, R.J.. An open-label trial of
N-acetylcysteine for the treatment of cocaine dependence: a pilot study. Prog.
Neuropsychopharmacol. Biol. Psychiatry 2007, 31, 389-394.
133. Martell, B.A.; Mitchell, E.; Poling, J. Gonsai, K.; Kosten, T.R.. Vaccine pharmacotherapy for the
treatment of cocaine dependence. Biol. Psychiatry 2005, 58, 158-164.
134. Gaval-Cruz, M.; Weinshenker, D. Mechanisms of disulfiram-induced cocaine abstinence:
antabuse and cocaine relapse. Mol. Interv. 2009, 9(4), 175-187.
135. Blaho, K.; Logan, B.; Winbery, S.; Park, L.; Schwilke, E. Blood cocaine and metabolite
concentrations, clinical findings, and outcome of patients presenting to an ED. Am. J. Emerg.
Med. 2000, 18, 593-598.
136. Beebe, D.K.; Walley, E. Substance abuse: the designer drugs. Am. Fam. Physician 1991, 43,
1689-1698.
137. Peroutka, S.J. Incidence of recreational use of 3,4-methylenedimethoxymethamphetamine
(MDMA, 'ecstasy') on an undergraduate campus. N. Engl. J. Med. 1987, 317, 1542-1543.
138. Webb, E.; Ashton, CH.; Kelly, P.; Kamali, F. Alcohol and drug use in UK university students.
Lancet 1996, 348, 922-925.
139. Buchert, R.; Thomasius, R.; Nebeling, B.; Petersen, K.; Obrocki, J.; Jenicke, L.; Wilke, F.;
Wartberg, L.; Zapletalova, P.; Clausen, M. Long-term effects of "ecstasy" use on serotonin
transporters of the brain investigated by PET. J. Nucl. Med. 2003, 44, 375-384.
140. Daws, L.; Irvine, R.J.; Callaghan, P.D.; Toop, P.N.; White, J.M.; Bochner, F. Differential
behavioural and neurochemical effects of para-methoxyamphetamine and 3,4-methylenedioxymethamphetamine in the rat. Prog. Neuropsychopharmacol. Biol. Psychiatry 2000, 24,
955-977.
141. Rattray, M. Ecstasy: Towards an understanding of the biochemical basis of the actions of
MDMA. Essays Biochem. 1991, 26, 77-87.
142. Ling, L.H.; Marchant, C.; Buckley, N.A.; Prior, M.; Irvine, R.J. Poisoning with the recreational
drug paramethoxyamphetamine (“death”). Med. J. Aust. 2001, 174, 453-455.
143. Liester, M.B.; Grob, C.S.; Bravo, G.L.; Walsh, R.N. Phenomenology and sequelae of 3,4methylenedioxymethamphetamine use. J. Nerv. Ment. Dis. 1992, 180, 345-352.
144. Zemishlany, Z.; Aizenberg, D.; Weizman A. Subjective effects of MDMA ('Ecstasy') on human
sexual function. Eur. Psychiatry. 2001, 16(2), 127-130.
145. Milroy, C.M.; Clark, J.J.C.; Forrest A.R. Pathology of deaths associated with ecstasy and “eve”
misuse. J. Clin. Pathol. 1996, 49, 149-153.
Pharmaceuticals 2010, 3
2358
146. Webb, C.; Williams, V. Ecstasy intoxication: appreciation of complications and the role of
dantrolene. Anaesthesia 1993, 48, 542-543.
147. Henry, J.A.; Jeffreys, K.J.; Dawling, S. Toxicity and deaths from 3,4metylenedioxymethamphetamine (“ecstasy”). Lancet 1992, 340, 384-387.
148. Gowing, L.R.; Henry-Edwards, S.M.; Irvine, R.J.; Ali R.L. The health effects of ecstasy : a
litterature review. Drug Alcohol Rev. 2002, 21, 53-63.
149. Dumont, G.J.; Kramers, C.; Sweep, F.C.; Touw, D.J.; van Hasselt, J.G.; de Kam, M.; van
Gerven, JM.; Buitelaar, JK.; Verkes, RJ. Cannabis coadministration potentiates the effects of
"ecstasy" on heart rate and temperature in humans. Clin. Pharmacol. Ther. 2009, 86(2),
160-166.
150. Lester, S.J.; Baggott, M.; Welm, S.; Schiller N.B.; Jones, R.T.; Foster, E.; Mendelson, J.
Cardiovascular effects of 3,4-methylenedioxymethamphetamine. A double-blind, placebocontrolled trial. Ann. Intern. Med. 2000, 133, 969-973.
151. Hegadoren, K.M.; Baker, G.B.; Bourin, M. 3,4-Methylenedioxy analogues of amphetamine:
defining the risks to humans. Neurosci. Biobehav. Rev. 1999, 23, 539-553.
152. Curran,
HV.;
Travill,
RA.
Mood
and
cognitive
effects
of
+/3,4methylenedioxymethamphetamine (MDMA, “ecstasy”): week-end high followed by mid-week
low. Addiction 1997, 92(7), 821-831.
153. Cohen, R.S.; Cocores, J. Neuropsychiatric manifestation following the use of 3,4methylenedioxymethamphetamine (MDMA: ecstasy). Prog. Neuropsychopharmacol. Biol.
Psychiatry 1997, 21, 727-734.
154. Benazzi, F.; Mazzoli, M. Psychiatric illness associated with ecstasy. Lancet 1991, 338, 1520.
155. Pallanti, S.; Mazzi D. MDMA (ecstasy) precipitation of panic disorder. Biol. Psychiatry 1992,
32, 91-95.
156. Obrocki, J.; Buchert, R.; Vaterlein, O.; Thomasius, R.; Beyer, W.; Schiemann, T. Ecstasy – long
term effects on the human central nervous system revealed by positron emission tomography. Br.
J. Psychiatry 1999, 175, 186-188.
157. Kish, S.J.; Furukawa, Y.; Ang, L.; Vorce, SP.; Kalasinski, KS. Striatal serotonin is depleted in
brain of a human MDMA (Ecstasy) user. Neurology 2000, 55, 294-296.
158. Bolla, K.I.; McCann, U.D.; Ricaurte, G.A. Memory impairment in abstinent MDMA (ecstasy)
users. Neurology 1998, 51, 1532-1537.
159. Wareing, M.; Fisk, J.E.; Murphy, P.N. Working memory deficits in current and previous users of
MDMA (“ecstasy”). Br. J. Psychol. 2000, 91, 181-188.
160. Hall, A.P. Ecstasy and the anaesthetist. Br. J. Anaest. 1997, 79, 697-698
161. Degenhardt, L.; Bruno, R.; Topp L. Is ecstasy a drug of dependence? Drug Alcohol Depend.
2010, 107(1), 1-10.
162. Topp, L.; Hando, J.; Dillon, P.; Roche, A.; Solowij, N. Ecstasy use in Australia: pattern of use
and assiociated harms. Drug Alcohol Depend. 1999, 55, 105-115.
163 Stein, D.J.; Rink, J. Effects of ecstasy blocked by serotonin reuptake inhibitors. J.
Clin..Psychiatry 1999, 60, 485.
Pharmaceuticals 2010, 3
2359
164. Rogers, G.; Elston, J.; Garside, R.; Roome, C.; Taylor, R.; Younger, P.; Zawada, A.; Somerville,
M. The harmful health effects of recreational ecstasy: a systematic review of observational
evidence. Health Technol. Assess 2009, 13(6), iii-iv, ix-xii, 1-315.
165. Methamphetamine use: 2002, 2003, 2004 and 2005, NSDUH Report; Substance Abuse and
Mental
Health
Services
Administration:
Rockville,
MD,
USA,
2007;
http://www.drugabusestatistics.samhsa.gov/2k7/meth/meth.pdf/, accessed on 21 July 2010.
166. Methamphetamine Use, Abuse, and Dependence: 2002, 2003, and 2004, NSDUH Report;
Substance Abuse and Mental Health Services Administration: Rockville, MD, USA, 2005;
http://www.drugabusestatistics.samhsa.gov/2k5/meth/meth.htm/, accessed on 21 July 2010.
167. Colfax, G.; Vittinghoff, E.; Husnik, M.J.; McKirnan, D.; Buchbinder, S.; Koblin, B.; Celum, C.;
Chesney, M.; Huang, Y.; Mayer, K.; et al., for the EXPLORE Study Team. Substance use and
sexual risk: a participant- and episode-level analysis among a cohort of men who have sex with
men. Am. J. Epidemiol. 2004, 59, 1002-1012.
168. Santos, A.P.; Wilson, A.K.; Hornung, C.A.; Polk, H.C., Jr.; Rodriguez, J.L; Franklin G.A.
Methamphetamine laboratory explosions: a new and emerging burn injury. J. Burn Care Rehabil.
2005, 26, 228-232.
169. Smoked Methamphetamine/amphetamine: 1992-2002; DASIS Report; Substance Abuse and
Mental
Health
Services
Administration:
Rockville,
MD,
USA,
2005;
http://www.oas.samhsa.gov/2k4/methSmoked/methSmoked.pdf/, accessed on 21 July 2010.
170. Methamphetamine abuse. Med. Lett. Drugs Ther. 2004, 46, 62-63.
171. Volkow, N.D.; Wang, G.J.; Fowler, J.S.; Logan, J.; Gatley, S.J.; Wong, C.; Hitzemann, R.
Pappas N.R. Reinforcing effects of psychostimulants in humans are associated with increases in
brain dopamine and occupancy of D(2) receptors. J. Pharmacol. Exp. Ther. 1999, 291, 409-415.
172. Shoptaw, S. Methamphetamine use in urban gay and bisexual populations. Top HIV Med. 2006,
14, 84-87.
173. McKetin, R.; Kelly E.; McLaren, J. The relationship between crystalline methamphetamine use
and dependence. Drug Alcohol Depend. 2006, 58, 198 – 204.
174. Buchanan, J.F.; Brown, C.R. “Designer drugs”. A problem in clinical toxicology. Med Toxicol
Adverse Drug Exp. 1988, 3, 1-17.
175. Turnipseed, S.D.; Richards, J.R; Kirk, J.D.; Diercks, D.B.; Amsterdam, E.A. Frequency of acute
coronary syndrome in patients presenting to the emergency department with chest pain after
methamphetamine use. J. Emerg. Med.. 2003, 24(4), 369-373.
176. Derlet, R.W.; Rice, P.; Horowitz, B.Z.; Lord, R.V. Amphetamine toxicity: experience with 127
cases. J. Emerg. Med. 1989, 7, 157-161.
177. Kaye, S.; Darke, S.; Duflou, J.; McKetin, R. Methamphetamine-related fatalities in Australia:
demographics, circumstances, toxicology and major organ pathology. Addiction 2008, 103(8),
1353-1360.
178. Sekine, Y.; Menibe, Y.; Ouchi, Y.; Takei, N.; Iyo, M.; Nakamura, K. ; Suzuki, K. ; Tsukada, H. ;
Okada, H. ; Yoshikawa, E. ; et al. Association of dopamine transporter loss in the orbitofrontal
and dorsolateralprefrontal cortices with methamphetamine-related psychiatric symptoms. Am. J.
Psychiatry 2003, 160, 1699-1701.
Pharmaceuticals 2010, 3
2360
179. Srisurapanont, M.; Jarusuraisin, N.; Kittirattanapaiboon, P. Treatment for amphetamine
dependence and abuse. Cochrane Database Syst. Rev. 2001, (4), CD003022.
180. Newton, T.F.; Roache, J.D.; De La Garza, R., 2nd. ; Fong, T.; Wallace, C.L.; Li, S.H. ; Elkashef,
A. ; Chiang, N. ; Kahn, R. Bupropion reduces methamphetamine-induced subjective effects and
cue-induced craving. Neuropsychopharmacology 2006, 31, 1537-1344.
181. Manghi, R.; Broers, B.; Benguettat, D.; Khazaal, Y; Khan, R; Zullino, D.F. Khat use: lifestyle or
addiction? J. Psychoactive Drugs 2009, 41(1), 1-10.
182. Al-Motarreb, A.; Baker, K.; Broadley, K.J. Khat: pharmacological and medical aspects and its
social use in Yemen. Phytother. Res. 2002, 16(5), 403-413.
183. Halket, J.M.; Karasu, Z.; Murray-Lyon, I.M. Plasma cathinone levels following chewing khat
leaves (Catha edulis Forsk.). J. Ethnopharmacol. 1995, 49(2), 111-113.
184. Widler, P.; Mathys, K.; Brenneisen, R.; Kalix, P.; Fisch, H.U. Pharmacodynamics and
pharmacokinetics of khat: a controlled study. Clin. Pharmacol. Ther. 1994, 55(5), 556-562.
185. Stefan, J.; Mathew, B. Khat chewing: an emerging drug concern in Australia? Aust N Z J
Psychiatry 2005, 39(9), 842-843.
186. Bhui, K.; Abdi, A. ; Abdi, M. ; Pereira, S.; Dualeh, M.; Robertson, D.; Sathyamoorthy, G.; Ismail
H. Traumatic events, migration characteristics and psychiatric symptoms among Somali
refugees-preliminary communication. Soc. Psychiatry Psychiatr. Epidemiol. 2003, 38(1), 35-43.
187. Brenneisen, R.; Fisch, H.U.; Koelbing, U.; Geisshusler, S.; Kalix, P. Amphetamine-like effects in
humans of the khat alkaloid cathinone. Br. J. Clin. Pharmacol. 1990, 30(6), 825-828.
188. Kalix, P. Khat: A Plant with Amphetamine Effects. J. Subst. Abuse Treat. 1988, 5, 163-169.
189. Ali, A.A.; Al-Sharabi, A.K.; Aguirre, J.M.; Nahas, R. A study of 342 oral keratotic white lesions
induced by qat chewing among 2500 Yemeni. J. Oral Pathol. Med. 2004, 33(6), 368-372.
190. Eriksson, M.; Ghani, N.A.; Kristiansson, B. Khat-chewing during pregnancy-effect upon the offspring and some characteristics of the chewers. East. Afr. Med. J. 1991, 68(2), 106-111.
191. Giannini, A.J.; Miller, N.S.; Turner, C.E. Treatment of Khat addiction. J. Subst. Abuse Treat.
1992, 9(4), 379-382.
192. Giannini, A.J; Nakoneczie, A.M. Treatment of Khat Addiction with Bromocriptine Mesylate: A
Case Report and Review of Cocaine- and Amphetamine-Like Effects. Am. J. Ther. 1995, 2(7),
487-489.
193. Friedman, R.A. The changing face of teenage drug abuse - The trend toward prescription drugs.
N. Engl. J. Med. 2006, 354, 1448-1450.
194. Kuehn, B.M. Prescription drug abuse rises globally. JAMA 2007, 297, 1306.
195. McCarthy, M. Prescription drug abuse up sharply in the USA. Lancet 2007, 369, 1505-1506.
196. Portenoy, R.K. Opioid therapy for chronic non-malignant pain: a review of critical issues. J. Pain
Symptom. Manage. 1996, 11, 203-217.
197. DuPont, RL. The brain and prescription drug abuse. In Balancing the Response to Prescription
Drug Abuse: Report of a National Symposium on Medicine and Public Policy; Wilford, B.B.,
Ed.; American Medical Association: Chicago, IL, USA, 1990.
198. Parran, T., Jr. Prescription drug abuse. A question of balance. Med. Clin. North Am. 1997, 81,
967-978.
Pharmaceuticals 2010, 3
2361
199. Adler, L.A.; Goodman, D.W.; Kollins, S.H.; Weisler, R.H.; Krishnan, S.; Zhang, Y.; Biederman,
J. Double-blind, placebo-controlled study of the efficacy and safety of lisdexamfetamine
dimesylate in adults with attention-deficit/hyperactivity disorder. J. Clin. Psychiatry 2008, 69,
1364-1373.
200. Mitler, M.M.; Hajdukovic, R. Relative efficacy of drugs for the treatment of sleepiness in
narcolepsy. Sleep 1991, 14, 218–220.
201. Van Geffen, E.C.; Hugtenburg, J.G.; Heerdink, E.R.; van Hulten, R.P.; Egberts, A.C.
Discontinuation symptoms in users of selective serotonin reuptake inhibitors in clinical practice:
tapering versus abrupt discontinuation. Eur. J. Clin. Pharmacol. 2005, 61, 303-307.
202. Compton, W.M.; Volkow, N.D. Abuse of prescription drugs and the risk of addiction. Drug
Alcohol Depend. 2006, 83 (Suppl. 1), S4-S7.
© 2010 by the authors; licensee MDPI, Basel, Switzerland. This article is an Open Access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).